In pseudohypoparathyroidism (PHP), PTH resistance results from impairment of signal transduction of G protein-coupled receptors caused by a deficiency of the Gsa-cAMP signaling cascade due to diminished Gsa activity in maternally imprinted tissues. In PHP-Ia, inactivating mutations of the GNAS gene lead to haploinsufficiency in some tissues with biallelic expression, so in addition to PHP, Albright's hereditary osteodystrophy (AHO) is also present. In PHP-Ib, caused by methylation defects at the GNAS locus, diminished Gsa activity was thought to be limited to maternally imprinted tissues, such as the renal proximal tubule and the thyroid, leading to a lack of AHO. Recently, we demonstrated methylation defects in patients with AHO signs, indicating a connection between epigenetic changes and AHO. Our objective was to determine Gsa activity in erythrocyte membranes in patients with epigenetic defects at the GNAS locus compared to normal controls and patients with inactivating GNAS mutations. Gsa activity and expression, mutation of the GNAS locus, and methylation status were studied in patients with PHP and mild signs of AHO (PHP-Ia: 12; PHP-Ib: 17, of which 8 had some features of AHO). Then, we statistically compared the Gsa activity of the different PHP subtypes. Patients with methylation defects at the GNAS locus show a significant decrease in erythrocyte Gsa activity compared to normal controls (PHP-Ib versus controls, p < .001). This was significantly lower in patients with AHO signs (PHP-Ib þ mild-AHO versus PHP-Ib, p < .05). Our research shows that PHP-Ia and PHP-Ib classification is not only overlapped genetically, as reported, but also in terms of Gsa activity. Reduced expression of GNAS due to methylation defects could downregulate Gsa activity in other tissues beyond those described and could also be causative of AHO. ß

Our work suggests that a trans-acting gene regulating the establishment or maintenance of imprinting at GNAS locus, if it exists, should be specific to PHP cases caused by epigenetic defects at GNAS.

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